BACKGROUND Infectious mononucleosis usually runs a mild self-limiting course. Complications arise rarely and when so, corticosteroids are the mainstay of their treatment. The role of antivirals in the management of severe EBV infections is debatable. METHODS We sought to review the usage of antivirals for severe EBV infection in apparently immunocompetent patients. For this reason a search in PubMed and Scopus was performed for the time period from 1982 to 2009. RESULTS 45 patients with severe manifestations of infectious mononucleosis received antivirals (as an adjunct to steroids in 26 of them). Specifically 21 patients with CNS involvement (meningoencephalitis, cerebellitis), 4 with peripheral nervous system involvement (Guillain-Barré, myeloradiculitis, facial nerve palsy), 5 with hepatitis and 15 with other afflictions (including adult respiratory distress syndrome, thrombocytopenia, aplastic anemia, acute renal failure, ulcerations, myocarditis, and frosted branch vasculitis) received antiviral medications. Thirty-nine out of these 45 patients had a favourable outcome (27 were cured and 12 showed clinical improvement) while 6 patients died. The most commonly prescribed antiviral regimen was acyclovir monotherapy (35 patients). Three patients received combinations of acyclovir with other antivirals and 1 received famciclovir. Three patients received ganciclovir monotherapy, 1 ganciclovir plus foscarnet, 1 foscarnet and 1 vidarabine. CONCLUSION The available data derive from case reports and case series and thus the deduction of conclusions regarding the effect, if any, of antiviral treatment is debatable. However, physicians may consider using antiviral agents in severe manifestations of EBV infections in immunocompetent patients as an adjunct to steroid treatment.